Acute Bacterial Meningitis in Infants and Children

ReviewAcute bacterial meningitis in infants and children Kwang Sik Kim Lancet Infect Dis 2010; 10: 32–42 Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA (Prof K S Kim MD) Correspondence to: Prof Kwang Sik Kim, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3157, Baltimore, MD 21287, USA [email protected] Bacterial meningitis continues to be an important cause of mortality and morbidity in neonates and children throughout the world. The introduction of the protein conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis has changed the epidemiology of bacterial meningitis. Suspected bacterial meningitis is a medical emergency and needs empirical antimicrobial treatment without delay, but recognition of pathogens with increasing resistance to antimicrobial drugs is an important factor in the selection of empirical antimicrobial regimens. At present, strategies to prevent and treat bacterial meningitis are compromised by incomplete understanding of the pathogenesis. Further research on meningitis pathogenesis is thus needed. This Review summarises information on the epidemiology, pathogenesis, new diagnostic methods, empirical antimicrobial regimens, and adjunctive treatment of acute bacterial meningitis in infants and children. Introduction Bacterial meningitis, an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space that happens in response to bacteria and bacterial products, continues to be an important cause of mortality and morbidity in neonates and children.1–4 However, mortality and morbidity vary by age and geographical location of the patient and the causative organism. Patients at risk for high mortality and morbidity include newborns, those living in low-income countries, and those infected with Gram-negative bacilli and Streptococcus pneumoniae.1–4 Severity of illness on presentation (eg, low score on Glasgow coma scale), infection with antimicrobialresistant organisms, and incomplete knowledge of the pathogenesis of meningitis are additional factors contributing to mortality and morbidity associated with bacterial meningitis.1–7 Suspected bacterial meningitis is a medical emergency; thus, immediate steps must be taken to establish the specific diagnosis, and empirical antimicrobial treatment must be started rapidly. The mortality of untreated bacterial meningitis approaches 100% and, even with optimum treatment, mortality and morbidity might happen. Neurological sequelae are relatively common in survivors of meningitis, particularly after pneumococcal meningitis.1–6 Epidemiology Almost all microbes that are pathogenic to human beings have the potential to cause meningitis, but a relatively small number of pathogens (ie, group B streptococcus, Escherichia coli, Listeria monocytogenes, Haemophilus influenzae type b [Hib], S pneumoniae, and Neisseria meningitidis) account for most cases of acute bacterial meningitis in neonates and children, although the reasons for this association remain incompletely understood. The absence of an opsonic or bactericidal antibody is a major risk factor in most cases of meningitis caused by group B streptococcus, E coli, Hib, S pneumoniae, and N meningitidis.8–12 Age-related incidence of Hib and N meningitidis disease is inversely related to prevalence of serum bactericidal activity,8,10 and the lack of type-specific 32 antibody is a major risk factor for neonatal group B streptococcal disease.11 Determinations of microbial targets capable of inducing opsonic or bactericidal antibodies and successful vaccination programmes with such targets in infants and children have changed the epidemiology of bacterial meningitis.13–18 However, microbial targets for opsonic or bactericidal antibodies have not been determined against all pathogens that commonly cause meningitis. The advancement of vaccine design in enhancing immunogenicity has been shown to be important in preventing meningitis caused by Hib, S pneumoniae, and N meningitidis. Protein-conjugated capsular polysaccharide vaccines have almost completely eliminated meningitis caused by vaccine serotypes. Routine immunisation in young infants and children with Hib conjugate vaccines has virtually eradicated meningitis due to these organisms in many high-income countries;13 in the USA, Hib meningitis happens primarily in children that are not immunised and among infants too young to have completed the primary immunisation series.14 Additionally, introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) has led to a substantial reduction in the incidence of pneumococcal meningitis in infants and children younger than 5 years.15–17 Use of these protein-conjugated vaccines has also reduced Hib and pneumococcal meningitis among unvaccinated populations through herd immunity. At present, limitations with PCV7 and meningococcal conjugate vaccines include an apparent increase in the incidence of invasive pneumococcal disease, including meningitis caused by non-PCV7 serotypes, such as serotype 19A (a penicillin and third-generation cephalosporin-resistant non-PCV7 serotype), and an apparent decline in bactericidal antibody against N meningitidis in infants, requiring a booster immunisation in the second year of life.17,18 Pathogenesis A relatively small number of microbial pathogens has been shown to account for most cases of meningitis in infants and children, but how those pathogens cross the blood–brain barrier and cause meningitis is incompletely www.thelancet.com/infection Vol 10 January 2010 40 but its contribution to Hib traversal of the blood–brain barrier is unclear.7. adeno-associated virus. pili. group B streptococcus.60.7. but the mature monomer is shown to be present on the cell surface and functions as a membrane receptor for the adhesive basement membrane protein laminin. as shown by partial inhibition of pneumococcal invasion of HBMEC by a PAFR antagonist.7.41 L monocytogenes penetration into the CNS has been attributed to transmigration of L monocytogenes-infected monocytes and myeloid cells across the blood–brain barrier.Review Bacterium Blood Brain endothelial cell Binding Brain Invasion Traversal Figure: Bacterial interaction with the blood–brain barrier.53 The monomer of RPSA (37 kDa laminin receptor protein) is a ribosomeassociated cytoplasmic protein and a precursor of the 67 kDa laminin receptor. it acts as a cellular receptor for L monocytogenes Vip.31 However. affecting different host signalling molecules.54 RPSA has also been shown to be a cellular target for various CNS-infecting microorganisms (table 1). contributing to penetration into the brain understood. hepatocyte growth factor.19 Transcellular traversal of the blood–brain barrier has been shown for most meningitis-causing pathogens in infants and children.7.thelancet.61 although the main route of L monocytogenes penetration into the CNS still needs to be determined.30. which include the receptor for the globular head of complement component C1q (gC1q-R) and Met tyrosine kinase. which is involved in infection of the spleen.30. www.57. For example.31 E coli invasion of HBMEC has also been shown to happen through other interactions with host receptors.33–37 The mechanism by which the same receptor is involved in CNS penetration by different organisms remains to be established. such as group B streptococcus and L monocytogenes.30 In addition.22.25–29 Meningitis-causing pathogens cross the blood–brain barrier transcellularly. Venezuelan equine encephalitis virus.62 PAFR has also been shown to interact with Hib (table 1).19 The E coli proteins that contribute to HBMEC binding (ie. liver.56 but whether these structures are unique to meningitis isolates of group B streptococcus is unclear.42 Several HBMEC receptors for InlB have been identified. group B streptococcus. InlB does not compete for the same interaction site on Met tyrosine kinase as the natural ligand.38. N meningitidis invasion of HBMEC is mediated by the outer membrane protein Opc binding to fibronectin. dengue virus. N meningitidis.25–29 For example. and brain of mice. and N meningitidis. However.32. paracellularly. and S pneumoniae (figure). Hib. 33 . CD48 and endoplasmin (formerly gp96).19.19. FbsA (fibrinogen-binding protein). and IagA (via lipoteichoic acid anchoring). FimH and OmpA) do so through interactions with their respective HBMEC receptors.20–23 The blood–brain barrier is a structural and functional barrier that is formed by brain microvascular endothelial cells.24 which protects the brain from any microbes and toxins circulating in the blood.58 but their contributions to L monocytogenes invasion of HBMEC remain incompletely understood. L monocytogenes invasion of HBMEC is mediated by internalin B (InlB).7.55.19 Experimental animal models and human cases of meningitis suggest that E coli and group B streptococcus penetrate the brain initially through the cerebral vasculature. possess several microbial structures that allow their binding to and invasion of HBMEC. including E coli. meningitis-causing pathogens.19. including E coli. including S pneumoniae. E coli penetration into the brain involves its binding to and invasion of the human brain microvascular endothelial cells (HBMEC) that constitute the blood–brain barrier.25–28 Recent studies have shown that microbial traversal of the blood–brain barrier happens via microbial interactions with host receptors (table 1).28.47–49 Endoplasmin is an endoplasmic reticulum paralogue of heat shock protein 90 that is also present on the surface of HBMEC.25.com/infection Vol 10 January 2010 endoplasmin also interacts with OmpA.50–52 For example. and prion protein. S pneumoniae.19.7. have been shown to cross the blood–brain barrier as live bacteria.39 and delayed translocation of pneumococci from the lung to the blood and from the blood to the cerebrospinal fluid (CSF) in PAFR-knockout mice. Other meningitis-causing pathogens. It is unclear how the laminin receptor is matured and synthesised from the laminin receptor protein.59 gC1q-R is also the HBMEC receptor for Plasmodium falciparum-infected erythrocytes (table 1). or by means of infected phagocytes (so-called Trojan horse mechanism). cytotoxic necrotising factor 1 (CNF1) interacts with 40S ribosomal protein subunit A (RPSA) on HBMEC. Group B streptococcal binding to HBMEC happens via Lmb (laminin-binding protein). S pneumoniae crosses the blood–brain barrier partly through interaction between cell-wall phosphorylcholine and the platelet-activating factor receptor (PAFR). and respiratory depression (Cushing’s triad) is a late sign of increased intracranial pressure.63 CD46 has also shown to be a receptor for measles. interleukin-8 secretion in response to E coli strain K1 happens in HBMEC. the symptoms and signs depend on the age of the child.70 Similar findings were seen for a group B streptococcus Lmb mutant. clinical features might include fever. lethargy. they might include fever. Hib=Haemophilus influenzae type b.Review Ligands References Endoplasmin Escherichia coli OmpA 30 Listeria monocytogenes Vip 31 37 kDa laminin receptor protein Escherichia coli CNF1 32 Neisseria meningitidis PilQ/PorA 33 Streptococcus pneumoniae CbpA 33 Hib Omp2 33 Prion protein ·· 34 Viruses (sindbis. 30% had bacterial meningitis.43 and lipo-oligosaccharides have been shown to contribute to a high-degree of bacteraemia and subsequent penetration into the CNS.71 In older children.19. Of note. For example. tick-borne encephalitis.38 In addition. or even absent. However. the mechanisms involved in microbial invasion of the blood–brain barrier differ from those involved in the release of cytokines and chemokines in response to meningitis-causing pathogens. In infants. nausea. bradycardia. hypothermia. although the release of interleukins 6 and 8 from HBMEC in response to bacterial invasion involves the p38 mitogen-activated protein kinase pathway. photophobia. Signs of meningeal irritation are present in 75% of children with bacterial meningitis at the time of presentation. Venezuelan equine encephalitis.53. and if there is no cardiopulmonary compromise.44–46 The involvement of host receptors and signaltransduction pathways in the microbial invasion of the blood–brain barrier might provide a new way to prevent and treat meningitis by the targeting of such host receptors or signalling molecules. and increased intracranial pressure. cytosolic phospholipase A2α) were efficient in preventing E coli penetration into the brain. confusion.19.64 and could indeed be used to prevent or treat meningitis.64–69 A proof-ofconcept study has shown that down-modulation of the HBMEC receptor for CNF1 (RPSA) and blockade or inhibition of host molecules involved in E coli invasion of HBMEC (eg. but not in non-brain endothelial cells (eg. In a study of neonatal meningitis.64 Recent studies suggest that this concept is also relevant to other meningitis-causing pathogens. respiratory distress. vomiting. seizures. or irritability. in a retrospective review of 326 children presenting to a paediatric emergency department in the Netherlands between 1988 and 1998 with signs of meningeal irritation. human 34 umbilical vein endothelial cells). variable.33. fever or hypothermia was noted in 62% of cases. E coli proteins involved in binding to and invasion of HBMEC did not affect the release of interleukin 8 from HBMEC. lethargy.73 Absence of meningeal irritation in children with bacterial meningitis was substantially more common in those younger than 12 months. Brudzinski’s sign (passive flexion of the neck elicits flexion of the hips). non-specific. adeno-associated) ·· 35–38 Streptococcus pneumoniae Phosphorylcholine 39 Hib Phosphorylcholine 40 Plasmodium falciparum Infected erythrocytes 41 Listeria monocytogenes InlB 42 Platelet-activating factor receptor gC1q-R CD46 Neisseria meningitidis Pili 43 Measles Haemagglutinin 44 Adenovirus Ad35 knob 45 Human herpesvirus 6 Glycoprotein H 46 CNF1=cytotoxic necrotising factor 1. and human herpesvirus 6 (table 1). or bulging fontanelles. focal neurological findings.com/infection Vol 10 January 2010 . However. but induced equal concentrations of interleukin 8 compared with the parent strain. poor feeding. Other signs of bacterial meningitis on physical examination include Kernig’s sign (flexing the hip and extending the knee to elicit pain in the back and legs).74 The constellation of systemic hypertension. and the host response to infection.7. Table 1: Blood–brain barrier receptors used by CNS-infecting microorganisms thereby anchoring the bacteria to the integrin α5β1 receptor on the cell surface. N meningitidis pili bind to CD46 on HBMEC.19. The clinical features of bacterial meningitis in infants and children can be subtle. N meningitidis invasion of HBMEC has been shown to involve c-Jun kinases 1 and 2.29 In addition. adenovirus. Evidence for mass www. Patients with suspected meningitis should receive a lumbar puncture after a mass lesion has been ruled out on clinical grounds or by CT scan of the head. diarrhoea.32. Diagnosis Clinical findings Bacterial meningitis requires early diagnosis and empirical antimicrobial treatment. which was defective for the invasion of HBMEC. irritability.thelancet. the duration of illness. vomiting. dengue. Laboratory findings CSF examination is of paramount importance for the diagnosis of all forms of meningitis (table 2). headaches.68 These findings suggest that targets for prevention of bacterial penetration into the brain differ from those involved in CNS inflammation associated with meningitis. gC1q-R=receptor for the globular head of complement component C1q.72 By contrast. and in four of 14 CSF samples that were culture-negative. 16 copies of L monocytogenes.80 In such children. In the presence of homologous antigen there is visible agglutination of the antibody-coated latex beads. and S pneumoniae. latex agglutination was positive in 49 (66%) of 74 CSF samples that grew S pneumoniae. In addition.82 whereas the sensitivity for broad-range 16S ribosomal DNA PCR was about 10–200 organisms per mL CSF. Real-time PCR has been shown to detect as few as two copies of E coli. Escherichia coli. microarray or biochip.81 In the multicentre pneumococcal meningitis surveillance study. PCR. and concentrations of protein and glucose are helpful in the differential diagnosis of various forms of meningitis (table 2). and a third of patients with listeria meningitis. Latex agglutination uses latex beads adsorbed with microbe-specific antibodies.6 CSF culture can be negative in children who receive antibiotic treatment before CSF examination.Review lesions will include focal neurological signs and evidence of increased intracranial pressure. and Haemophilus influenzae type b.com/infection Vol 10 January 2010 Opening pressure (cm H20) White blood cells (×10⁶ cells per L) Glucose (mg/dL) Protein (mg/dL) Common >20 >1000 <10 >100 Less common <20 Bacteria* 5–1000 10–45 50–100 Mycobacterium tuberculosis Common >20 100–500 Less common <20 5–100 Common <20 100–500 Less common <20 5–100 10–45 <10 >100 50–100 Borrelia burgdorferi 10–45 <10 50–150 >150 Treponema pallidum Common <20 Less common <20 5–500 >500 10–45 <10 50–150 >150 Fungi Common Variable Less common Variable 5–500 >500 10–45 <10 >100 50–100 Viruses Common <20 Less common <20 5–500 >500 Normal 10–45 50–100 >100 *Group B streptococci. which amplifies DNA under isothermal conditions (63°C). half of patients with Gramnegative bacillary meningitis. Table 2: Likely pathogens for CNS infections on the basis of cerebrospinal fluid analysis previously received antibiotics.thelancet. is a promising tool. loop-mediated isothermal amplification method. increased CSF white blood cell counts and increased CSF protein concentration are usually sufficient to establish the diagnosis of bacterial meningitis. because it does not need thermocycling apparatus and the results can be read with the naked eye (based on turbidity or colour development by SYBR Green dye for 35 . complete sterilisation of N meningitidis from CSF happened within 2 h of giving a parenteral thirdgeneration cephalosporin and the beginning of sterilisation of S pneumoniae from CSF by 4 h into treatment. Listeria monocytogenes.6 The use of standard or sequential-multiplex PCR has been shown to be useful in identification of infecting pathogens in patients who have previously received antibiotics or in resource-poor settings. the limit of detection differs between assays. Such tests include latex agglutination. but less sensitive with N meningitidis antigen.86 which might provide more rapid and accurate diagnosis of bacterial infection in infants and children. or whose initial CSF Gram stain is negative with negative culture at 72 h incubation.85 The time needed for the whole process from DNA extraction to the end of real-time PCR was 1·5 h.75–78 Gram stain is positive in about 90% of children with pneumococcal meningitis.78. Streptococcus pneumoniae. Neisseria meningitidis. A Gram stain of CSF will show whether bacteria are present. and immunochromatography (table 3). Non-culture methods Non-culture tests should be considered for patients who need earlier identification of pathogens or have previously received antibiotics.79 CSF cell count and differential. N meningitidis.82–87 Multiplex realtime PCR or broad-range PCR aimed at the 16S ribosomal RNA gene of eubacteria is promising for the detection of pathogens from CSF. Blood cultures or non-culture diagnostic tests might help in identifying the infecting pathogen. particularly in resource-poor settings. A low CSF white blood cell count with positive Gram stain is a risk factor for an unfavourable outcome.87 A recently developed nucleic-acid amplification technique. and a positive Gram stain shows bacterial counts higher than 1×10³ cells per mL in CSF.82 an attractive timeframe for its application in clinical practice. and 28 copies of group B streptococcus. The detection rate was substantially higher with PCR than with cultures in patients who had www. A Gram-stain-specific probe-based real-time PCR using 16S ribosomal RNA has been shown to allow simultaneous detection and discrimination of clinically relevant Grampositive and Gram-negative bacteria directly from blood samples.84. loop-mediated isothermal amplification. For example. about 80% of children with meningococcal meningitis. sequential PCR-based serotyping of S pneumoniae using serotype-specific primers could improve ascertainment of pneumococcal serotype distribution in settings in which prior use of antibiotics is high. Latex agglutination assays have been sensitive towards Hib antigen. and CSF pressure should be recorded during the lumbar puncture.75–78 Cytospin centrifugation increases the chances of detecting organisms in Gramstained CSF.82 However. and bactericidal antibiotics should be administered intravenously at the highest clinically validated doses to patients with suspected bacterial meningitis.7 36 Antimicrobial treatment Eradication of the infecting organism from the CSF is entirely dependent on antibiotics. empirical treatment for patients with bacterial meningitis in areas where resistant S pneumoniae strains are prevalent must include the addition of vancomycin (panel).95 Because bacterial meningitis is defined as inflammation that happens in response to bacteria and bacterial products. and 5·5% of meningitis cases happened without pleocytosis. blood neutrophil count of at least 10×10⁹ cells per L.105 Therefore. β-lactams and vancomycin) have decreased penetration into CSF in the absence of meningeal inflammation.90–92 However. whereas a regimen for Gram-negative bacilli with a high likelihood of resistance (eg. For example.88. Selection of empirical antimicrobial regimens is designed to cover the likely pathogens. this proposed diagnostic tool only achieved 95% sensitivity. with modifications if CSF Gram stain is positive. gentamicin).95 For example.94. whereas hydrophilic agents (ie. five patients with bacterial meningitis who had pleocytosis were found to have a bacterial meningitis score that indicated low risk.93 Compared with CSF culture (sensitivity of 71%) and latex agglutination (86%). and hybridisation of labelled DNA with oliogonucleotide probes (pathogenspecific or virulence genes) immobilised on a microarray. potentially useful in resource-poor settings Microarray or biochip90–92 Not yet Requires a suitable biochip Immunochromatography93 Not yet Highly sensitive for Streptococcus pneumoniae Table 3: Non-culture diagnostic tests for identification of pathogens for meningitis staining nucleic acids).102–104 An important factor in the choice of empirical antimicrobial agents is the emergence of antimicrobialresistant organisms. fluoroquinolones and rifampicin) penetrate relatively well into the CSF even if the meninges are not inflamed. and proteinbinding ability of drugs.102. patients with CSF culture positivity without pleocytosis or increased CSF protein concentrations are presumably representative of the early stages of bacterial meningitis. amplification of targeted DNA. and outpatient management might be considered for children who had pleocytosis (7×10⁶ cells per L or more) and none of the following five criteria on presentation: history of a seizure with the illness. molecular weight. CSF protein of at least 80 mg/dL.97 Several retrospective and prospective studies showed that delay in antibiotic treatment was associated with adverse outcomes. www. and many of the penicillin-resistant pneumococci have reduced susceptibility to third-generation cephalosporins (ie. and Gram-negative bacilli that are resistant to many β-lactam drugs. and efflux transporters.96. inflammation of the meninges. the prevalence of S pneumoniae strains that are relatively resistant to penicillin (minimum inhibitory concentration [MIC] 0·1–1·0 μg/mL) or highly resistant to penicillin (MIC greater than 1·0 μg/mL) is increasing. or CSF neutrophil count of at least 1×10⁹ cells per L. The ability of an antimicrobial agent to penetrate the blood–brain barrier is the most important factor that determines whether efficient bacterial killing happens in the CSF. including S pneumoniae that is resistant to penicillin or third-generation cephalosporins. penetration of vancomycin into the CSF can be reduced in the absence of meningeal inflammation and also in patients who receive adjunctive dexamethasone treatment.98–101 In patients with suspected bacterial meningitis for whom immediate lumbar puncture is delayed due to pending brain imaging study or the presence of disseminated intravascular coagulation. A rapid immunochromatographic test for S pneumoniae was evaluated in 122 children with pneumococcal meningitis. Bacterial meningitis score The ability to distinguish between bacterial and nonbacterial aseptic meningitis in infants and children in the emergency department could contribute to limiting hospital admissions or unnecessary use of antibiotics.97 Treatment failures in bacterial meningitis as a result of multiresistant organisms have been reported. suggesting that immunochromatography might be useful in the diagnosis of pneumococcal meningitis. Treatment of patients at risk of infection with L monocytogenes must include a synergistic regimen containing ampicillin and an aminoglycoside (eg. However.com/infection Vol 10 January 2010 .88 but its use in the diagnosis of bacterial meningitis has not been tested.103 Lipophilic agents (ie. cefotaxime and ceftriaxone). Identification of pathogens by use of a microarray or biochip involves extraction of genomic DNA from CSF.thelancet. Blood–brain-barrier penetration is affected by lipophilic property. its usefulness in clinical practice has not been shown.96. based on age of the patient and specific risk factors (table 4).81 Yes Sensitive with Haemophilus influenzae type b. However.Review Clinical application Comments Latex agglutination78. but less sensitive with Neisseria meningitidis PCR82–87 Not yet Need to develop specific and broad targets or primers Loop-mediated isothermal amplification88. blood cultures must be obtained and antimicrobial treatment should be initiated immediately. positive CSF Gram stain.89 The assay detected ten or more copies of S pneumoniae in oral mucosa swab samples. nosocomial meningitis) should include an aminoglycoside (eg.89 Not yet Does not require thermocycling apparatus. immunochromatography was 100% sensitive for the diagnosis of pneumococcal meningitis. The bacterial meningitis score has been developed for assessing infants and children with meningitis. 115 These findings support the use of a thirdgeneration cephalosporin for meningococcal meningitis in areas where penicillin resistance is prevalent. and thus cannot be used as monotherapy for bacterial meningitis. and has been shown to be uniformly susceptible to β-lactam antibiotics (eg. studies have reported isolates of group B streptococcus with penicillin MICs of 0·12–1·0 μg/mL that had mutations in the target penicillin-binding proteins similar to the mechanisms involved in penicillin-resistant S pneumoniae. gatifloxacin was as effective as the combination of ceftriaxone and vancomycin against a highly cephalosporin-resistant pneumococcal strain in an experimental meningitis model. gatifloxacin. including penicillin against group B streptococcus. and continued monitoring of antimicrobial susceptibility patterns. immunodeficiency.108 However.thelancet. including cerebral palsy and mental retardation. relative resistance to penicillin (MIC 0·1 μg/mL) has been shown to occur in 3–4% of the meningococcal isolates in the USA and in 2% of the 137 isolates recovered between 2000 and 2006 from equatorial sub-Saharan Africa (the so-called meningitis belt). Hib 3–6 months No immunisation S pneumoniae.113 By contrast. Table 4: Likely pathogens for meningitis based on age and immunisation status garenoxacin).97.127 37 . For example.116–124 For example.106 Antibacterial killing activity in CSF also depends on the bacterial burden at the start of treatment.96. diabetes mellitus (S pneumoniae. Similarly.120 Moxifloxacin and garenoxacin had CSF bacterial killing rates that exceeded those found with the combination of ceftriaxone and vancomycin against experimental meningitis caused by vancomycin-tolerant S pneumoniae. MICs of β-lactam antibiotics. For example. group B streptococcus is commonly responsible for neonatal bacterial meningitis. and developmental delay. terminal complement deficiencies. is thus important. However. The penetration of intravenously given aminoglycosides into the CSF remains variable or poor even in the presence of meningeal inflammation. freshmen living in dormitories.114. ertapenem). cochlear implant.102. and thus penicillin is at present the drug of choice for invasive group B streptococcal infection including meningitis. and include hearing loss. caused by group B streptococcus and S pneumoniae) who have many organisms on CSF Gram stain are likely to yield 10⁷–10⁸ organisms per mL. otitis. some patients with bacterial meningitis (eg. The MIC and minimum bactericidal concentration are established in laboratories by use of bacterial inoculum size of 10⁴–10⁵ organisms per mL.126 Hearing loss happens in 22–30% of survivors of pneumococcal meningitis compared to 1–8% after meningococcal meningitis. including newer agents. Listeria monocytogenes). Listeria monocytogenes (neonatal pathogens) 1–3 months No immunisation or one dose of primary immunisation Neonatal pathogens. www. Hib S pneumoniae (non-PCV serotypes).106. but they might be useful if other drugs cannot be used.109. N meningitidis.112 A recent study in Spain reported an increased incidence in penicillin non-susceptible strains of N meningitidis (eg. outbreaks (Neisseria meningitidis). N meningitidis Risk factors for specific pathogens are as follows: cerebrospinal fluid leak. penicillin MIC 0·1 μg/mL or less). sinusitis (S pneumoniae.125 Adjunctive treatment Neurological sequelae are common in survivors of meningitis. gemifloxacin. cognitive impairment.121 Fluoroquinolones are not recommended for use in children younger than 18 years because of concerns about their effects on growing cartilage in experimental animals. HIV infection. The potential roles of newer β-lactam antibiotics (meropenem. S pneumoniae. penicillin has been the standard treatment for meningococcal meningitis. and lipopeptides (daptomycin) in the treatment of meningitis caused by resistant bacteria have been shown in animal models of experimental meningitis.110 The optimum empirical regimen for meningitis caused by penicillin non-susceptible group B streptococci that includes third-generation cephalosporins has not been established. Haemophilus influenzae type b [Hib]). recently developed quinolones (moxifloxacin.111. clinical effectiveness of these newer antimicrobial drugs as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of S pneumoniae has not been established. dexamethasone did not substantially affect the penetration of gemifloxacin and moxifloxacin into the CSF. nephrotic syndrome (Streptococcus pneumoniae). Antimicrobial susceptibility patterns must be established for all organisms isolated from the CSF. MICs 0·1–0·5 μg/mL) from 9·1% in 1986 to 71·4% in 1997. were increased 1000 times when the inoculum size increased from 10⁴ to 10⁸ organisms per mL. Of interest.6.107 Careful monitoring of the response to antimicrobial treatment is therefore warranted for patients with bacterial meningitis who have high bacterial burden on the basis of initial CSF Gram stain.Review amikacin) plus a third-generation or fourth-generation cephalosporin. N meningitidis >7 months to 5 years No immunisation Primary immunisation completed 6–21 years S pneumoniae.76 and MIC values can be 100–1000-times higher than would normally be expected. Escherichia coli. For example. PCV=pneumococcal conjugate vaccine. Hib At least two doses of primary immunisation (with Hib-Omp vaccine) S pneumoniae. with an implication of treatment failures. sickle-cell disease.124 However. N meningitidis. but penicillin resistance has evolved. at least until penicillin susceptibility is known.119. or meropenem. N meningitidis S pneumoniae. N meningitidis.6. asplenia. the Metropolitan Atlanta Developmental Disabilities Surveillance Program in 1991 identified bacterial meningitis as the leading postnatal cause of developmental disabilities. cefepime.com/infection Vol 10 January 2010 Likely pathogens <1 month Group B streptococci. including hippocampal apoptosis in experimental animals with pneumococcal and E coli meningitis who received dexamethasone. positive Gram stain) 3 months to 21 years Cefotaxime (75 mg/kg every 6–8 h.132 Another issue with adjunctive dexamethasone treatment is the possibility of neuronal injury. Success with the protein-conjugate Hib and S pneumococcus PCV vaccines in the prevention of meningitis shows that identification of conserved targets for opsonic or bactericidal antibodies is likely to enhance the development of effective vaccination programmes for the prevention of meningitis caused by N meningitidis and other meningitis-causing bacteria. particularly for patients with meningitis caused by pneumococci that are resistant to third-generation antibiotics. up to a maximum of 600 mg daily) can be added in the setting of administration of dexamethasone In a 2007 Cochrane review. secondary fever (recurrence of fever after at least 24 h without fever) happens more commonly in patients treated with dexamethasone than in those who are not (52% vs 24%. Another important consideration for the treatment of bacterial meningitis is the substantial morbidity in survivors of meningitis. individuals living in low-income countries. Dexamethasone given shortly before or when antibiotics were first given has been shown to reduce the rate of hearing loss in children with Hib meningitis. by age Less than 1 month Ampicillin (50–100 mg/kg every 6 h) plus gentamicin (2·5 mg/kg every 8 h). and such cases should be treated with dexamethasone as well as vancomycin and ceftriaxone. Most meningitiscausing pathogens cross the blood–brain barrier. fever curve) can be complicated by the use of dexamethasone.134 Long-term follow-up studies are thus needed to address the effect of dexamethasone treatment on any cognitive and neuropsychological outcomes in patients with bacterial meningitis. in whom bacteriological killing in the CSF depends on vancomycin. multi-resistant Gram-negative bacilli). its use as adjunctive treatment in children with bacterial meningitis.6 In addition. is promising. Emergence of antimicrobial-resistant bacteria presents a constant challenge to the development of new bactericidal antibiotics for the treatment of bacterial meningitis.130 The widespread use of dexamethasone in children with bacterial meningitis needs careful monitoring of clinical (eg.129 The American Academy of Pediatrics Committee on Infectious Diseases suggests that dexamethasone treatment might be considered for infants and children older than 6 weeks with pneumococcal meningitis after considering the potential benefits and possible risks.6. and infections caused by antimicrobial-resistant pathogens (eg. Advances in microbial genome sequencing and functional genomic approaches are likely to be beneficial in the identification of such microbial targets. or rifampicin (10 mg/kg every 12 h. but its beneficial effects on hearing and other neurological sequelae are not as clear against meningitis caused by other organisms. up to a maximum 1 g per dose).thelancet. p=0·0009). 95% CI 0·31–0·76) compared with placebo. involving specific interactions of microbial structures www. CSF bactericidal activity has been shown in children who have meningitis due to cephalosporin-resistant pneumococci. partly because of our incomplete knowledge on the pathogenesis of neurological sequelae associated with bacterial meningitis.Review Panel: Empirical antimicrobial regimen for treatment of bacterial meningitis. and lower rates of severe hearing loss and long-term neurological sequelae.133. adjunctive treatment with dexamethasone was associated with lower case mortality. particularly for those infections in newborns. particularly in resource-limited settings.131 However.128 The beneficial effect of adjunctive dexamethasone treatment was evident in adults with bacterial meningitis. concomitant giving dexamethasone and vancomycin can reduce penetration of vancomycin into the CSF by virtue of the antiinflammatory activity of dexamethasone. wide availability. A recent multicentre. up to a maximum of 4 g daily) plus vancomycin (15 mg/kg every 6 h. fever curve. cephalosporinresistant pneumococcus) or organisms that are difficult to treat (eg. and because of its safety. low cost. or vancomycin (15 mg/kg every 6 h) can be added in the setting of suspected pneumococcal meningitis (eg. up to a maximum of 12 g daily) or ceftriaxone (50 mg/kg every 12 h. New information available on the pathogenesis of meningitis is likely to be useful for the prevention and treatment of bacterial meningitis. Monitoring of the clinical response (eg. double-blind randomised study in six Latin American countries showed that adjunctive treatment with oral glycerol (1·5 g/kg every 6 h for 48 h) prevents severe neurological sequelae in childhood meningitis (odds ratio 0·31. resulting in 38 treatment failure.com/infection Vol 10 January 2010 . resolution of symptoms and signs) and bacteriological responses to antimicrobial treatment. and oral administration. or cefotaxime (50 mg/kg every 6–8 h) can be used in the setting of suspected Gram-negative bacilli 1–3 months Ampicillin (50–100 mg/kg every 6 h) plus cefotaxime (75 mg/kg every 6–8 h) or ceftriaxone (50 mg/kg every 12 h).135 Glycerol is a hyperosmolar agent. For example. Future challenges Bacterial meningitis continues to be an important cause of mortality and morbidity throughout the world. effective strategies to prevent morbidity are lacking at present. 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